Drug and Medication-Induced Rheumatic Diseases

Overview

• Timing: typically months to years of exposure to the offending medication
• Clinically: resembles primary systemic lupus erythematosus but less association with renal disease
• Labs: antinuclear antibody and anti-histone antibody positivity is common 
  • Rarely positive SSA and dsDNA have been described (usually with the use of TNF alpha inhibitors) 
  • Hematologic abnormalities less frequent in drug-induced lupus
  • Hypocomplementemia is uncommon (except for quinidine-induced forms)

Subtypes of Drug-Induced Lupus

Systemic Lupus Erythematosus

Mild arthralgia, myalgia, serositis, and constitutional symptoms are common.

• High risk medications
  • Hydralazine
  • Procainamide
• Moderate risk medications
  • Isoniazid
  • Quinidine
• Low risk medications
  • Minocycline
  • Tumor necrosis factor-α (TNF-α) inhibitors
  • Pyrazinamide
  • Propylthiouracil
  • Sulfasalazine
  • Methyldopa
  • Captopril
  • Acebutolol
  • D-Penicillamine
  • Carbamazepine
  • Oxcarbazepine
  • Phenytoin
  • Propafenone
  • Chlorpromazine
  • Minoxidil

Subacute Cutaneous Lupus Erythematosus

Most common drug-induced lupus subtype.

• Antiepileptics:
  • Carbamazepine
  • Phenytoin
• Angiotensin-converting enzyme inhibitors
• Calcium channel blockers 
• Chemotherapeutic agents
• Hydrochlorothiazide
• Leflunomide
• Proton-pump inhibitors 
• Statins
• Terbinafine
• TNF-α inhibitors

Chronic Cutaneous Lupus Erythematosus

• Rare but discoid lesions have been reported.
• Fluorouracil compounds or their modern derivatives, such as capecitabine, have been associated with chronic cutaneous drug-induced lupus.

Treatment

• Discontinuation of the offending agent
• NSAIDs and low dose steroids may be helpful while waiting for symptoms to resolve, which typically occurs within 1-3 weeks.
• If symptoms persist past 1 month, the condition has likely become chronic.

HMG-CoA Reductase Inhibitors (Statins)

• Myalgia>myositis
• Statins can unmask or worsen an underlying autoimmune myopathy.
• Risk factor: lipophilic statins (simvastatin, atorvastatin, lovastatin) >>  hydrophilic counterparts (pravastatin, rosuvastatin, fluvastatin)
• Management: consider switching to different statin

Immune Checkpoint Inhibitors (ICIs)

• Prevalence <1%, but case- fatality rate >20%; risk factor: multiple ICIs
• Onset: 1 wk to 6 mos
• Proximal, symmetric weakness and pain
• Monitor for concurrent myositis and/or myasthenia gravis
• Biopsy: myofiber necrosis
• Management: high dose immunosuppression determined by internal organ involvement and severity

Colchicine

• Risk factor: higher doses, CYP P450 drug interactions, renal dysfunction
• Muscle biopsy: necrosis and fibers with autophagic vacuoles

Corticosteroids

• Risk factors: prolonged use, high doses
• Usually with muscular atrophy
• Typically does not cause an elevation in CK

Fibrates

• Can produce a spectrum of manifestations that include asymptomatic serum creatine kinase elevation, myalgias, exercise-induced pain, rhabdomyolysis, and myoglobinuria

Other Meds

• Amiodarone
• Antimalarial drugs: very rare, can be with dysphagia, EM biopsy shows: myeloid and curvilinear bodies, management: stop antimalarial drug, may improve but usually not to baseline
  • Chloroquine
  • Hydroxychloroquine
  • Quinacrine
• D-penicillamine
• Interferon alpha
• Ipecac
• Procainamide emetine
• Vincristine

Toxins That Can Cause Myopathy

• Alcohol, amphetamines, cocaine, heroin, phencyclidine, and meperidine
• Can see widespread muscle breakdown, rhabdomyolysis, and myoglobinuria

Zidovudine (AZT) and Other Nucleoside Reverse Transcriptase Inhibitors

• Months after med start
• Risk factor: doses >600 mg/day
• Mild CK elevation
• Myopathic on EMG
• Muscle biopsy: ragged red fibers, indicative of mitochondrial inclusions
• Management: drug cessation
• Prognosis: symptoms improve within 4 wks of holding the drug

Overview

• Drug-induced vasculitis primarily involves small- and medium-sized blood vessels, and the clinical manifestations are like those of other idiopathic vasculitides. 
• Almost any medication can be implicated in drug-induced vasculitis, and the clinical manifestations range from single organ involvement (most commonly, skin) to life-threatening multi-organ disease.
• Clinical manifestations range from arthralgias to isolated cutaneous rashes to severe single or multi-organ involvement.
• There are no unique pathologic or laboratory aspects of drug-induced vasculitis that differentiate it from other vasculitides.
• Withdrawal of the offending agent is the most important step in management, but more severe cases may require immunosuppressive therapy.

Drug-Associated Vasculitides Classified by Vessel Size Involvement

Below are commonly reported drug-associated vasculitides classified by vessel size involvement.

Large Vessel Drug-Induced Vasculitis 

Type of vasculitis that affects the aorta and its major branches

• Granulocyte colony-stimulating factor (aortitis)
• Immune checkpoint inhibitors (aortitis)
• Amphetamines (cerebral vasculitis)
• Cocaine (cerebral vasculitis)

Medium Vessel Drug-Induced Vasculitis

Vasculitis that predominantly affects the medium arteries, such as the main visceral arteries and their branches

• Empagliflozin
• Gemcitabine
• Metolazone
• Minocycline

Small Vessel Drug-Induced Vasculitis

Type of vasculitis that predominantly affects intraparenchymal arteries, arterioles, capillaries, and venules

a. ANCA-Associated Vasculitis
Typically associated with an atypical ANCA or MPO-ANCA, but antibodies against elastase and lactoferrin are commonly reported. End-organ damage, including necrotizing glomerulonephritis and alveolar hemorrhage, are less frequent.

• Allopurinol
• Cocaine contaminated with levamisole
• D-penicillamine
• Hydralazine
• Immune checkpoint inhibitors
• Isoniazid
• Methimazole
• Phenytoin
• Propylthiouracil
• Sulfasalazine
• TNF-inhibitors

b. IgA Vasculitis 
Immune complex-mediated, small vessel vasculitis with IgA1-dominant immune deposits

• Antibiotics
• Furosemide
• NSAIDs
• Statins
• TNF-inhibitors
• Warfarin

c. Leukocytoclastic Vasculitis
Onset of skin rash within 1–3 wks after drug initiation

• Allopurinol
• Amiodarone
• Antibiotics
• Anti-tuberculosis drugs
• Immune checkpoint inhibitors
• NSAIDs
• Sulfonamides
• TNF-inhibitors
• Valproic acid
• Warfarin
• Zidovudine (AZT) and didanosine (hypersensitivity angiitis)

d. Peripheral Vasculitic Neuropathy
Clinical presentation includes mononeuropathy, mononeuritis multiplex, or sensorimotor polyneuropathy

• Amphetamines
• Immune checkpoint inhibitors
• Leflunomide
• Minocycline
• Phenytoin
• TNF-inhibitors

Overview

• Serum sickness is an immune complex-mediated reaction to injections of foreign serum or protein that occurs 1 to 2 weeks after exposure or sooner if there has been a previous exposure.
• Serum sickness-like reaction presents clinically very similarly to serum sickness, but does not involve the formation of immune complexes.
• Manifests as fever, rash, joint pain, and joint swelling in a symmetrical distribution
• May occur with many medications, but penicillin is a common cause.
• Meds that can cause serum sickness or serum sickness-like reactions:
  • Anti-venom injections (for venomous snake bites, etc.)
  • Antibiotics: penicillins, sulfonamides
  • Anti-epileptics: phenytoin, carbamazepine
  • Rheum drugs: allopurinol, rituximab, infliximab
• Infections like streptococcus and hepatitis B can cause serum-sickness like reactions.

Treatment

• NSAIDs and supportive care